Prana Details Data Showing That PBT2 Reduces Cognitive Impairment Caused by Tau
Protein Accumulation
Summary of New Data Presented at the 11th International Conference on
Alzheimer's and Parkinson's Disease
MELBOURNE, AUSTRALIA -- (Marketwire) -- 03/08/13 -- Prana
Biotechnology (NASDAQ: PRAN) (ASX: PBT). Following on from the
announcement released on 4th March, 2013 and at the request of the
Australian Securities Exchange, the company is pleased to provide
further detail in respect to the presentation of the new data
demonstrating the ability of PBT2 to reduce the damage to brain
cells, caused by the accumulation of the tau protein and preventing
subsequent cognitive impairment.
The data was generated in an animal model that overproduces the tau
protein giving rise to 'tangle like' inclusions similar to those
which cause neuronal death in Alzheimer's disease (AD). Importantly,
whilst the anti-aggregation effects of PBT2 on Abeta have been well
documented(1), these results were generated in a model which is
independent of the presence of Abeta, indicating that PBT2 has the
ability to prevent neuronal damage via multiple metal mediated
pathways, including Abeta and tau aggregation.
The data is being presented by Prana scientist Associate Professor
Paul Adlard on 9th March 2013 in his presentation entitled, "Metal
Chaperones are novel therapeutic agents for tauopathy".
"These findings provide further evidence that by targeting specific
metal imbalances in the brain, PBT2 possesses the ability to
ameliorate Alzheimer's pathology in relevant mouse models for both
senile plaques and neurofibrillary tangles. This data, in combination
with the previously reported Phase IIa clinical trial results(2) for
PBT2 in Alzheimer's disease further support PBT2 as a potentially
promising therapy for this devastating disease", commented Rudy
Tanzi, the Joseph P. and Rose F. Kennedy Professor of Neurology at
Harvard Medical School and Prana's Chief Scientific Advisor.
Associate Professor Robert Cherny, Prana's Head of Research,
commented, "Prana scientists have shown that the Metal Protein
Attenuating Compound, PBT2 improves cognitive impairment, Abeta
burden and tau hyperphosphorylation in the APP/PS1 transgenic mouse
model of AD which overexpresses Abeta(1).
Recent literature supports
the notion that metals modulate the properties of tau and may affect
the formation of neurofibrillary tangles (NFTs)(3,4,5) which are a
feature of several neurodegenerative diseases. In human beings,
certain mutations in the gene encoding the tau protein lead to
hereditary fronto-temporal dementia (FTD) and Parkinsonism
collectively known as tauopathies. Indeed AD itself has been defined
as an "A&#946;-mediated tauopathy".
PBT2 is currently in a 12 month Phase II Alzheimer's disease clinical
trial, the IMAGINE trial, which is now fully enrolled and will be
completed at the end of the year.
Experimental Methodology
The rTg(tauP301L)4510 mouse line(6) is a
transgenic mouse model of human tauopathy. From an early age
rTg(taup301L)4510 mice display neurofibrillary tangles (NFT) like
pathology in the neocortex which progresses into the hippocampus and
limbic structures with increasing age. This is manifested
biochemically by an age-dependent transition of accumulating tau
species from soluble 55 kDa to insoluble hyperphosphorylated 64 kDa.
The mice develop significant cognitive impairments from 4 months of
age. In our study, rTg(tauP301L)4510 mice (n=10-15/group) were aged
to approximately 12 months at which time they were administered
either vehicle or PBT2 (30mg/kg) by daily oral gavage for six weeks.
Prior to culling and tissue collection the cognitive performance of
the animals was examined using a standard test of cognition, the
Y-maze. A stereological analysis of NFT burden and neuron number was
conducted by histology and other biochemical endpoints assessed by
Western blot.
Results
Administration of PBT2 resulted in
significant improvement in performance in the Y maze, a significant
reduction in the number of NFTs and a significant increase in
cortical and hippocampal neurons in the rTg(tauP301L)4510 mouse
model. A significant increase in the levels of the PP2A protein
(implicated in tau phosphorylation events) in PBT2 treated animals
suggest that the drug may directly act upon biochemical pathways
which lead to NFT formation as well as any potential interaction with
tau itself(4).
References
(1) Adlard P, et al (2008) Rapid
restoration of cognition in Alzheimer's transgenic mice with
8-hydroxy quinoline analogs is associated with decreased interstitial
Abeta. Neuron 59:43-5510.
(2) Lannfelt et al. Safety, efficacy, and
biomarker findings of PBT2 in targeting A&#946; as a modifying
therapy for Alzheimer's disease: a Phase IIa, double-blind,
randomised, placebo-controlled trial. Lancet Neurology (2008) vol. 7,
pp. 779-86. Lannfelt et al. Errata: Lancet Neurology (2009) vol. 8,
pp. 981.
(3) Insook K, et al (2011) Zinc stimulates tau S214
phosphorylation by the activation of Raf/mitogen-activated protein
kinase-kinase/extracellular signal-regulated kinase pathway.
Neuroreport: 22:839-844.
(4) Craddock TJA et al, The Zinc
Dyshomeostasis Hypothesis of Alzheimer's Disease. PLoSOne e33552.
doi:10.1371/journal.pone.0033552.
(5) Xiong et al (2013) Zinc induces
protein phosphatase 2A inactivation and tau hyperphosphorylation
through Src dependent PP2A (tyrosine 307) phosphorylation. Neurobiol
Aging. 34:745-56.
(6) Ramsden M et al (2005) Age-Dependent
Neurofibrillary Tangle Formation, Neuron Loss, and Memory Impairment
in a Mouse Model of Human Tauopathy (P301L). J Neurosci, 25:
10637-10647.
About Prana Biotechnology Limited
Prana Biotechnology was
established to commercialize research into age-related
neurodegenerative disorders. The Company was incorporated in 1997 and
listed on the Australian Securities Exchange in March 2000 and listed
on NASDAQ in September 2002. Researchers at prominent international
institutions including The University of Melbourne, The Mental Health
Research Institute (Melbourne) and Massachusetts General Hospital, a
teaching hospital of Harvard Medical School, contributed to the
discovery of Prana's technology.
For further information please visit the Company's web site at
www.pranabio.com.
Forward Looking Statements
This press release contains
"forward-looking statements" within the meaning of section 27A of the
Securities Act of 1933 and section 21E of the Securities Exchange Act
of 1934. The Company has tried to identify such forward-looking
statements by use of such words as "expects," "intends," "hopes,"
"anticipates," "believes," "could," "may," "evidences" and
"estimates," and other similar expressions, but these words are not
the exclusive means of identifying such statements. Such statements
include, but are not limited to any statements relating to the
Company's drug development program, including, but not limited to the
initiation, progress and outcomes of clinical trials of the Company's
drug development program, including, but not limited to, PBT2, and
any other statements that are not historical facts. Such statements
involve risks and uncertainties, including, but not limited to, those
risks and uncertainties relating to the difficulties or delays in
financing, development, testing, regulatory approval, production and
marketing of the Company's drug components, including, but not
limited to, PBT2, the ability of the Company to procure additional
future sources of financing, unexpected a
dverse side effects or
inadequate therapeutic efficacy of the Company's drug compounds,
including, but not limited to, PBT2, that could slow or prevent
products coming to market, the uncertainty of patent protection for
the Company's intellectual property or trade secrets, including, but
not limited to, the intellectual property relating to PBT2, and other
risks detailed from time to time in the filings the Company makes
with Securities and Exchange Commission including its annual reports
on Form 20-F and its reports on Form 6-K. Such statements are based
on management's current expectations, but actual results may differ
materially due to various factions including those risks and
uncertainties mentioned or referred to in this press release.
Accordingly, you should not rely on those forward-looking statements
as a prediction of actual future results.
Contacts:
Australia
Prana Biotechnology
+61 3 9349 4906
US
Leslie Wolf-Creutzfeldt
T: 646-284-9472
E: leslie.wolf-creutzfeldt@grayling.com